Résumé
The heme-regulated inhibitor (HRI), a member of the eIF-2 kinase family is crucial for regulating protein synthesis during stress. In addition to heme, stress proteins Hsp90 and Hsp70 are known to regulate HRI. The present study aims to determine the physical association of these Hsps in the regulation of HRI activation during oxidative stress using human K562 cells as a model. Extracts from the stress-induced cells were used for determining HRI kinase activity by measuring eIF-2 phosphorylation, and Hsp-HRI interaction by immunoprecipitation and immunoblot analyses. The results indicate a significant increase in both Hsp70 and Hsp90 expression during AAPH (2, 2’-azobis (2-amidinopropane) dihydrochloride)-induced oxidative stress. Further, their interaction with HRI, which correlates well with its increased HRI kinase activity leads to inhibition of protein synthesis. Thus, we demonstrate that Hsps play an important role in the regulation of initiation of protein synthesis during oxidative stress.
Sujets)
Amidines/composition chimique , Amidines/pharmacologie , Animaux , Activation enzymatique/effets des médicaments et des substances chimiques , Protéines du choc thermique HSP70/métabolisme , Protéines du choc thermique HSP90/métabolisme , Hémine/pharmacologie , Humains , Interactions hydrophobes et hydrophiles , Espace intracellulaire/effets des médicaments et des substances chimiques , Espace intracellulaire/métabolisme , Cellules K562 , Stress oxydatif/effets des médicaments et des substances chimiques , Phosphorylation/effets des médicaments et des substances chimiques , Biosynthèse des protéines/effets des médicaments et des substances chimiques , Espèces réactives de l'oxygène/métabolismeRésumé
The impact of interamidine distance on antileishmanial activity of new aryldiamidines have been evaluated against amastigotes of L. donovani in hamster. Of the 20 compounds tested, only four (2,8-diamidino-9,10-dihydrodibenzoxepin; 2,7-diamidinoxanthone; 2,7-diamidinothioxanthone and 2,7-diamidinoxanthene) showed significant inhibition (more than 80%) of multiplication of amastigotes in spleen. The interamidine distance in the structure appears to have bearing on antileishmanial activity. The observations made are likely to evoke new understanding on the structure activity relationship of diarylamidines.